# Effect of Iron Deprivation on H. pylori-induced Gastric Carcinogenesis

> **NIH NIH P01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $460,322

## Abstract

PPG PROJECT 1 SUMMARY
H. pylori is the strongest risk factor for gastric cancer. One microbial determinant that augments cancer risk is the
cag type IV secretion system (T4SS) which exports an oncoprotein, CagA, into epithelial cells. Dietary factors
also modify cancer risk and we have shown with Projects 2 and 3 and Cores A and B that iron depletion
enhances the ability of H. pylori to induce carcinogenesis in transgenic INS-GAS mice and Mongolian gerbils.
Metabolomics studies with Core B subsequently identified increased gastric mucosal levels of the secondary
carcinogenic bile acid deoxycholic acid (DCA) only among H. pylori-infected iron-depleted mice. These discovery-
driven results informed provocative in vivo intervention studies with Project 2 and Core A demonstrating that
DCA accelerates H. pylori-induced carcinogenesis. Mechanistically, our groups have shown that DCA 1) endows
H. pylori with an enhanced capacity to translocate CagA, 2) induces gastric epithelial expression of
proinflammatory chemokines, 3) activates the epidermal growth factor receptor (EGFR), and 4) induces epithelial
proliferation. With Projects 2, 3, and Core A, we also demonstrated that iron deficiency enhances H. pylori
colonization within gastric stem cell niches, suggesting that aberrant signaling within a susceptible stem cell
population may lower the threshold for carcinogenesis. Long-lived gastric epithelial stem cells are marked by
Leucine-rich repeats and immunoglobulin-like domains 1 (Lrig1) and, pertinent to this application, we have 1)
used lineage tracing to demonstrate that cag+ strains selectively activate Lrig1 in vivo, leading to the development
of premalignant lesions, and 2) developed primary gastric organoid models to show that H. pylori-induced Lrig1
expression is partially dependent on EGFR activation. Finally, we have full access to a unique prospective cohort
in Colombia where gastric adenocarcinoma and H. pylori infections are endemic. Full clinical, endoscopic, and
histologic data are available at baseline and at each interval follow-up out to 26 years, including frozen gastric
tissue from the 20- and 26- year timepoints from persons who either progressed histologically or remained
stable, providing a unique opportunity to define disease mechanisms. Our hypothesis is that effectors such as
DCA synthesized under iron-deficient conditions promote oncogenic interactions between H. pylori cag+
strains and Lrig1 stem cells that contribute to augmentation in gastric cancer risk. Our Aims are to:
1. Define effects of DCA on Lrig1 pathobiology within the context of H. pylori-induced carcinogenesis in vivo
2. Use primary multicellular systems to mechanistically study effects of DCA on Lrig1-driven phenotypes in
 conjunction with human validation
3. Define effects of DCA on H. pylori microbial function that influence carcinogenesis

## Key facts

- **NIH application ID:** 10767084
- **Project number:** 2P01CA116087-17
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** RICHARD M. PEEK
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $460,322
- **Award type:** 2
- **Project period:** 2009-01-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10767084

## Citation

> US National Institutes of Health, RePORTER application 10767084, Effect of Iron Deprivation on H. pylori-induced Gastric Carcinogenesis (2P01CA116087-17). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10767084. Licensed CC0.

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